Use of Continuous Infusions of Eptifibatide and Cangrelor in Large Vessel Occlusion Acute Ischemic Stroke After Emergent Carotid Artery Stenting

Case Report J Neurol Res. 2020;10(3):99-103

Shaheryar Hafeeza, Pegah Ghamasaeea, c, Sharmin Amjadb, Colleen Bartholb, Ramesh Grandhia

Abstract Keywords: Internal carotid artery dissection; Middle cerebral artery occlusion; Emergent internal carotid artery stent; Eptifibatide; Can- Placement of carotid stents in the setting of large vessel occlusion grelor; P2Y12; GP IIb/IIIa; Ischemic stroke (LVO) is sometimes necessary in patients with steno-occlusive disease of the extracranial internal carotid artery (ICA) or ICA dissection. Use of antiplatelet agents is required to prevent in-stent thrombosis; however, after an LVO, a decompressive hemicraniectomy may Introduction be necessary. After placement of a carotid stent, a fine balance must be obtained between preventing stent-related thromboembolic com- According to the American Heart Association/American Stroke plications while also maintaining the possibility of quickly and safely Association (AHA/ASA), ischemic stroke accounts for 87% of performing a decompressive hemicraniectomy, if indicated. In this all strokes in the USA. It is the fifth leading cause of death case, we discuss the novel use of continuous eptifibatide and cangre- in the USA and is the leading cause of serious long-term dis- lor infusions after carotid stent placement to maintain stent patency, ability [1]. The current acute interventions for acute ischemic while preserving the option of emergent hemicraniectomy. A 55-year- stroke include administration of intravenous (IV) recombinant old man presented with left hemispheric ischemic symptoms due to tissue plasminogen activator (rtPA), intra-arterial administra- flow failure from a left ICA dissection. He underwent emergent angi- tion of rtPA, and endovascular mechanical thrombectomy [2]. ography with angioplasty and stenting of the petrous and ascending In up to 10% of large ischemic strokes involving the cervical segments of the left ICA. The procedure was complicated by middle cerebral artery (MCA), severe post-ischemic cerebral an embolization of thrombus to a left middle cerebral artery (MCA) edema may occur, leading to increased intracranial pressure M2 division branch, resulting in an occlusion, which could not be and herniation that carries up to an 80% mortality risk [3, 4]. opened. The patient was placed on short acting intravenous antiplate- Decompressive hemicraniectomy has been shown in a meta- let agents (eptifibatide infusion for 60 h and cangrelor infusion for 24 analysis of seven randomized controlled trials to significantly h) for prevention of in-stent thrombosis while under close observation decrease the mortality of patients suffering from large MCA- for potential neurologic decline and need for decompressive hemi- territory strokes [5]. Consequently, the AHA/ASA made a class craniectomy. After 84 h of observation, the patient did not experi- I recommendation stating that decompressive hemicraniecto- ence a decline and the antiplatelet infusions were discontinued after my in patients < 60 years of age with unilateral MCA territory he received aspirin and a loading dose of clopidogrel. Intravenous infarcts who deteriorate neurologically within 48 h is effective eptifibatide or cangrelor infusions are short-acting antiplatelet options [6]. Though the optimal trigger or time point for performing that can be used in patients with acute ischemic stroke from LVO in surgery is unknown, consensus exists that surgery should be the setting of ICA stent placement when there exists a potential for performed before clinical signs of brainstem compression [6]. decompressive hemicraniectomy. Carotid artery dissection is a known cause of ischemic stroke and, in the context of endovascular intervention, some- Manuscript submitted April 23, 2020, accepted April 27, 2020 times requires balloon angioplasty with or without concomi- Published online May 30, 2020 tant stent placement. The AHA scientific statement on indica- tions for the performance of endovascular neurointerventional aDepartment of Neurosurgery, University of Texas Health Science Center at procedures suggests class IIb evidence that endovascular San Antonio, TX, USA revascularization by intravascular balloon angioplasty and/ bDepartment of Pharmacy Services, Neurosurgical Intensive Care Unit, Uni- or stenting may be considered for patients with symptomatic versity Health System, San Antonio, TX, USA severe intracranial stenosis (70% luminal narrowing) despite cCorresponding Author: Pegah Ghamasaee, Department of Neurosurgery, Uni- versity of Texas Health Science Center, 7703 Floyd Curl Drive, MC 7843, San optimal medical therapy [7]. The scientific statement made no Antonio, TX 78229-3900, USA. Email: [email protected] comment on the timing of revascularization. In a large multicenter retrospective study, the emergent use of carotid artery doi: https://doi.org/10.14740/jnr591 stents in combination with anterior circulation thrombectomy

Articles © The authors | Journal compilation © J Neurol Res and Elmer Press Inc™ | www.neurores.org This article is distributed under the terms of the Creative Commons Attribution Non-Commercial 4.0 International License, which permits 99 unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited Eptifibatide and Cangrelor Infusions After ICA Stenting J Neurol Res. 2020;10(3):99-103

Figure 1. Diagnostic cerebral angiogram (AP view) demonstrating Figure 2. Diagnostic cerebral angiogram (AP view) following balloon critical left ICA stenosis associated with the dissection in the ascending angioplasty and stent placement in the ascending cervical segment of cervical segment of the left ICA prior to balloon angioplasty and stent- the left ICA, showing significantly improved contrast opacification of the ing (arrow). ICA: internal carotid artery; AP: anteroposterior. artery (arrow). ICA: internal carotid artery; AP: anteroposterior. was effective and safe for the treatment of acute stroke [8]. onset. Computed tomography (CT) angiography of the head Placement of a stent requires long-term oral dual antiplatelet and neck was unrevealing for large vessel occlusion (LVO) therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor to within the intracranial circulation but demonstrated a left ICA prevent in-stent thrombosis due to the inherent thrombogenic- dissection within the ascending cervical segment of the ICA ity of intravascular stents. To combat periprocedural thrombo- causing critical stenosis. He was taken for endovascular inter- sis complications, some clinicians opt to use IV glicoprotein vention where balloon angioplasty was performed, and follow- (GP) IIb/IIIa receptor inhibitors as a bridge for transitioning to ing IV eptifibatide bolus at a dose of 90 µg/kg, two 4.5 × 20 an oral P2Y12 receptor inhibitor [9]. mm Neuroform EZ® (Stryker Neurovascular, Freemont, CA, In the case discussed herein, our patient presented with USA) stents were placed across the dissected segment of the left hemispheric symptoms from an acute carotid dissection. left ICA (Figs. 1, 2). Balloon angioplasty and stenting were performed within the After the angioplasty and placement of the stents, throm- extracranial left ICA for revascularization, but the procedure bus was visualized within the distal aspect of the left MCA M1 was complicated by embolization of thrombus to the inferior division and revascularization of this segment was performed division left MCA. IV eptifibatide was administered during the via thrombectomy; however, despite numerous attempts and procedure immediately prior to stent placement. However un- administration of intra-arterial tPA, the left MCA inferior divi- successful, attempts were made to open up the left M2 inferior sion M2 artery remained occluded. division branch. Following the procedure, we did not transition The patient was brought to the neurosurgical intensive the patient to oral DAPT due to concern that the patient may care unit on an eptifibatide infusion running at 2 µg/kg/min. warrant decompressive hemicraniectomy secondary to infarct Follow-up CT imaging demonstrated the expected left MCA and swelling from the left M2 occlusion. We treated the patient infarct involving the temporoparietal lobes resulting from the with IV eptifibatide and cangrelor until we were confident that inferior division M2 occlusion (Fig. 3). Due to the large area the patient did not require surgery. This is the first report on the of infarct and the patient’s young age, he was observed closely use of cangrelor, a reversible P2Y12 receptor inhibitor, in the for neurologic deterioration or clinical signs of brainstem com- peri-operative period within the neurosurgical literature. pression, which would warrant decompressive hemicraniectomy. The patient was started on a hypertonic saline infusion tar- Case Report geting a serum sodium concentration of 150 - 155 mmol/L. The patient reached the target within 44 h. We elected not to A 55-year-old, right-handed man presented to our institution start the patient on oral DAPT during this period and instead with left hemispheric symptoms with National Institutes of continued the IV eptifibatide infusion for the first 3 days post Health Stroke Scale (NIHSS) score of 22. IV tPA was admin- stroke. At the 3 day mark (the critical time point of maximal istered due to the patient presenting within 4.5 h of symptom cerebral edema with the highest risk for requiring a decom-

100 Articles © The authors | Journal compilation © J Neurol Res and Elmer Press Inc™ | www.neurores.org Hafeez et al J Neurol Res. 2020;10(3):99-103

hibition of platelet aggregation and thrombus formation. Ep- tifibatide is Food and Drug Administration (FDA) approved for treatment of acute coronary syndrome managed medi- cally or with percutaneous coronary intervention (PCI), and management of PCI with or without intracoronary stenting to reduce the risk of acute cardiac ischemic events (death and/ or myocardial infarction (MI)). Additionally, cangrelor, a non- thienopyridine adenosine triphosphate analogue, is the only IV antagonist of the P2Y12 receptor exhibiting rapid, potent, predictable, and reversible platelet inhibition with quick offset of effect [10]. Cangrelor is currently indicated as an adjunct to PCI to reduce the risk of MI, repeat coronary revascularization, and stent thrombosis in patients who have not been treated with a P2Y12 platelet inhibitor and are not being given a GP IIb/IIIa inhibitor [11]. The platelet GP IIb/IIIa receptor is the final common path- way leading to the binding of fibrinogen to the activated platelet GP IIb/IIIa and thrombus formation. GP IIb/IIIa is therefore a logical therapeutic target for prevention of ischemic complications during percutaneous coronary procedures. Despite the benefits seen in trials with coronary intervention using these agents, limited data has adapted the use of GP IIb/IIIa inhibitors in carotid arterial stenting. Qureshi et al reported on the safety of eptifibatide as an adjunct to carotid angioplasty and Figure 3. Head CT (axial view) exhibiting hypodensity within the left stent placement (CAS) for extracranial carotid artery stenosis temporal lobe of the brain, consistent with the left M2 inferior division [12]. Eptifibatide was administered IV as two 180 µg/kg bolus occlusion (thick arrow). The scan, performed less than 36 h out from doses, and then as a 2 µg/kg/min infusion for 20 - 24 h. Among the revascularization procedure, already demonstrates subtle midline the 25 patients who underwent the procedure, no intracerebral shift and mass effect from the area of infarcted brain (thin arrow). CT: computed tomography. hemorrhage and one minor ischemic stroke occurred during the 1-month follow-up period. One episode of major bleeding from the femoral insertion site required surgical repair and pressive hemicraniectomy), we discontinued the eptifibatide blood transfusion. The authors concluded that eptifibatide ad- infusion and switched to a continuous infusion of cangrelor ministered as an adjunct to CAS seems to be safe. Eptifibatide’s at a rate of 4 µg/kg/min for 24 h. Approximately 84 h after pharmacokinetic parameters include immediate onset of action ictus, after we felt confident that the patient would not require after initial bolus (> 80% inhibition of adenosine diphosphate surgical intervention, the patient was loaded with 300 mg (ADP)-induced aggregation achieved 5 min after bolus) with clopidogrel and 325 mg aspirin and the cangrelor infusion was maximal effect within 1 h. Platelet function is restored 4 - 8 h subsequently discontinued. CT angiography performed 6 days following discontinuation, and its elimination half-life is 2.5 h. after presentation revealed patency of the carotid stents with Finally, it is recommended to discontinue eptifibatide at least asymptomatic petechial hemorrhage of the infarction. Over the 2 - 4 h prior to coronary artery bypass graft surgery [13]. next several days, the patient’s clinical exam slowly improved Most reports of GP IIb/IIIa inhibition during CAS feature and he was discharged to inpatient rehabilitation. the use of abciximab, a monoclonal antibody with a half-life of 10 min, but an effect on platelets lasting for almost 48 h. Discussion Kapadia et al performed a study in 151 consecutive, high- surgical-risk patients: 128 received abciximab and 23 controls were given only heparin. There were more adverse procedural The occurrence of thrombus formation immediately after ca- events in the control group (8%; one major stroke and one neu- rotid arterial injury and stenting and the need for emergent de- rological death) compared with the abciximab group (1.6%; compressive hemicraniectomy provide the rationale for early one minor stroke and one retinal infarction; P = 0.05). At 30- IV antiplatelet therapy. The accepted practice of DAPT was day follow-up, one patient presented with delayed intracranial not followed immediately post-stent placement in this case hemorrhage (ICH) in the abciximab group [14]. Qureshi et al because of the risk of requirement of a decompressive hemi- prospectively examined 70 patients: 37 given abciximab as an craniectomy. Although there is no literature on the matter, there adjunct to high-risk carotid stenting versus 33 patients with is a general consensus among neurosurgeons to not perform standard intraprocedural heparinization. The 3% frequency of cranial surgery on patients taking DAPT due to the possibility ischemic stroke in the high-risk patients given IV abciximab of uncontrolled bleeding during surgery. Our patient was man- was lower than controls; however, the benefit was lost because aged with two short acting IV antiplatelet agents, eptifibatide of the higher rate (5%) of ICH [15]. Further studies are needed and cangrelor. Eptifibatide is a cyclic peptide derivative that to determine the appropriate role of abciximab in this patient reversibly binds the GP IIb/IIIa receptors, with subsequent in- population.

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Similarly, there is a paucity of data on the use of continu- Data Availability ous infusion cangrelor in the setting of CAS in acute ischemic stroke. Following a cangrelor IV bolus and infusion, platelet inhibition occurs within minutes and the average half-life is 3 The data supporting the findings of this study are available - 6 min. In healthy volunteers, a 30 µg/kg bolus followed by a from the corresponding author upon reasonable request. 4 µg/kg/min infusion provided extensive inhibition of platelet aggregation 2 min after the bolus dose, and 80% of subjects References returned to near-baseline platelet activity within 60 min [16]. These pharmacokinetic properties of cangrelor make it an at- 1. Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das tractive option to consider for bridging patients to surgery in SR, Deo R, de Ferranti SD, et al. Heart disease and stroke whom discontinuation of antiplatelet therapy, particularly a statistics-2017 update: a report from the American Heart P2Y12 inhibitor, can lead to catastrophic consequences while Association. Circulation. 2017;135(10):e146-e603. preserving normal hemostasis at the time of surgery. Pharma- 2. Chaudhary N, Pandey AS, Gemmete JJ. Interven- codynamic studies demonstrate a substantial interaction when tion in acute cerebral ischaemic stroke: a review of the a thienopyridine loading dose is administered during cangre- role of pharmacological therapies and intra-arterial lor infusion. Specifically, the antiplatelet effect of a- clopi mechanical thrombectomy devices. Postgrad Med J. dogrel loading dose is substantially attenuated when given in 2011;87(1032):714-723. the midst of the infusion (and therefore will not provide the 3. Hacke W, Schwab S, Horn M, Spranger M, De Georgia anticipated P2Y12 inhibition once the infusion is discontin- M, von Kummer R. 'Malignant' middle cerebral artery ued), likely because the labile, short lived active metabolite of territory infarction: clinical course and prognostic signs. clopidogrel cannot bind to the P2Y12 receptor when it is occu- Arch Neurol. 1996;53(4):309-315. pied by cangrelor [17]. Therefore, a clopidogrel loading dose 4. Berrouschot J, Sterker M, Bettin S, Koster J, Schneider should be administered at the end of the cangrelor infusion. D. Mortality of space-occupying ('malignant') middle cer- Given the much shorter half-life of cangrelor and potential ebral artery infarction under conservative intensive care. need for emergent surgery, we transitioned our patient from the Intensive Care Med. 1998;24(6):620-623. eptifibatide infusion to cangrelor, followed by a clopidogrel 5. Alexander P, Heels-Ansdell D, Siemieniuk R, Bhatnagar loading dose and maintenance therapy with clopidogrel and N, Chang Y, Fei Y, Zhang Y, et al. Hemicraniectomy ver- aspirin daily. Our case is novel because we demonstrated that sus medical treatment with large MCA infarct: a review long-term use of continuous IV infusions of eptifibatide (60 h) and meta-analysis. BMJ Open. 2016;6(11):e014390. and cangrelor (24 h) can be done safely and effectively while 6. Wijdicks EF, Sheth KN, Carter BS, Greer DM, Kasner preserving the option of emergent cranial surgery. SE, Kimberly WT, Schwab S, et al. Recommendations for the management of cerebral and cerebellar infarction Acknowledgments with swelling: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014;45(4):1222-1238. None to declare. 7. Meyers PM, Schumacher HC, Higashida RT, Barnwell SL, Creager MA, Gupta R, McDougall CG, et al. Indi- Financial Disclosure cations for the performance of intracranial endovascular neurointerventional procedures: a scientific statement from the American Heart Association Council on Car- None to declare. diovascular Radiology and Intervention, Stroke Council, Council on Cardiovascular Surgery and Anesthesia, Inter- disciplinary Council on Peripheral Vascular Disease, and Conflict of Interest Interdisciplinary Council on Quality of Care and Out- comes Research. Circulation. 2009;119(16):2235-2249. None to declare. 8. Behme D, Mpotsaris A, Zeyen P, Psychogios MN, Kow- oll A, Maurer CJ, Joachimski F, et al. Emergency stenting of the extracranial internal carotid artery in combi- Informed Consent nation with anterior circulation thrombectomy in acute ischemic stroke: a retrospective multicenter study. AJNR Informed consent was obtained. Am J Neuroradiol. 2015;36(12):2340-2345. 9. Qureshi AI. Adjunctive use of platelet glycoprotein IIb/ IIIa inhibitors for carotid angioplasty and stent placement: Author Contributions time to say good bye? J Endovasc Ther. 2003;10(1):42- 44. PG and SA prepared the manuscript. SH, RG and CB per- 10. Ferreiro JL, Ueno M, Angiolillo DJ. Cangrelor: a review formed revisions and approved the final version for submis- on its mechanism of action and clinical development. Ex- sion. pert Rev Cardiovasc Ther. 2009;7(10):1195-1201.

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